Predictors of Virologic and Clinical Outcomes in HIV-1–Infected Patients Receiving Concurrent Treatment with Indinavir, Zidovudine, and Lamivudine: AIDS Clinical Trials Group Protocol 320

Predictors of Virologic and Clinical Outcomes in HIV-1–Infected Patients Receiving Concurrent Treatment with Indinavir, Zidovudine, and Lamivudine: AIDS Clinical Trials Group Protocol 320

From University of Rochester School of Medicine and Dentistry, Rochester, New York; Harvard School of Public Health, Boston, Massachusetts; University of Washington, Seattle, Washington; Johns Hopkins University, Baltimore, Maryland; University of North Carolina, Chapel Hill, North Carolina; University of California, San Diego, California; University of Alabama at Birmingham, Birmingham, Alabama; University of Miami School of Medicine, Miami, Florida; and Columbia University, New York, New York.

Abstract

Background: A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure.

Objective: To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy.

Design: Observational analysis of one treatment group in a phase III trial.

Setting: 40 AIDS Clinical Trials units.

Patients: 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 × 10⁹ cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8.

Measurements: HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death.

Results: Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2–log₁₀ copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1–to 1.99–log₁₀ copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1–log₁₀ copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2–log₁₀ copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1–to 1.99–log₁₀ copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1–log₁₀ copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count ≥ 0.10 × 10⁹ cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 × 10⁹ cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 × 10⁹ cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 × 10⁹ cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 × 10⁹ cells/L or greater (compared with <0.05 × 10⁹ cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]).

Conclusions: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Article and Author Information

Note: Drs. Demeter and Hughes contributed equally to this work.
Disclosures: Dr. Demeter has received research support from Merck & Co. and Pharmacia-Upjohn and research support and honoraria from Glaxo Wellcome and Roche Molecular Systems and has served as a consultant to Glaxo Wellcome, Roche Pharmaceuticals, and Roche Molecular Systems. Dr. Hughes has received research support from Roche Pharmaceuticals and served as a consultant to Chiron. Dr. Jackson received an honorarium from Glaxo Wellcome. Dr. Fiscus has received research support from Glaxo Wellcome, Organon Technika, and Visible Genetics. Dr. Squires has received research support from Merck & Co., Abbott Laboratories, Agouron Pharmaceuticals, Bristol-Myers Squibb, Glaxo Wellcome, Gilead Sciences, Systemix, and Oxo-Chemie and has served as a consultant to Merck & Co., Bristol-Myers Squibb, Roxane, and Vertex. Dr. Fischl has received research support from Abbot Laboratories, Bristol-Myers Squibb, and Dupont and research support and honoraria from Agouron Pharmaceuticals, Glaxo Wellcome, and Merck & Co. and has served as an advisory board member to Bristol-Myers Squibb and Glaxo Wellcome.
Acknowledgments: The authors thank the patients and investigators at the 33 AIDS Clinical Trials units and 7 National Hemophilia Foundation sites, whose participation made this study possible. They also thank Luis Berrios, Michael Chiulli, and Robin Shepard for performance of HIV-1 RNA assays.
Grant Support: In part by the AIDS Clinical Trials Group and grants (AI-27658, AI-38855, AI-38858 [contracts 96VC006, 96VC009, 96VC010], AI-27664, AI-30731, RR-00044) from the U.S. National Institutes of Health. Supplemental support for some virology studies was provided by Merck & Co. and Roche Molecular Systems. Study medications were provided by Merck & Co. and Glaxo Wellcome.
Requests for Single Reprints: Lisa M. Demeter, MD, Infectious Diseases Unit, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 689, Rochester, NY 14642.
Current Author Addresses: Dr. Demeter: Infectious Diseases Unit, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 689, Rochester, NY 14642.
Drs. Hughes and Bosch: Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115.
Dr. Jackson: Department of Pathology, Johns Hopkins University, 600 North Wolfe Street, Carnegie 420, Baltimore, MD 21287.
Dr. Coombs: Department of Laboratory Medicine, University of Washington, 1959 Northeast Pacific Avenue, Room NW 120, Seattle, WA 98195.
Ms. Grimes: Brown University, Box G8063, Providence, RI 02906.
Dr. Fiscus: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, 709 Mary Ellen Jones Building, Campus Box 7140, Chapel Hill, NC 27599.
Dr. Spector: Department of Pediatrics, Division of Infectious Diseases, University of California, San Diego, 9500 Gilman Drive, Room 430, La Jolla, CA 92093.
Dr. Squires: Los Angeles County University of Southern California Medical Center, Rand Schrader Clinic, 1300 North Mission Road, Room 349, Los Angeles, CA 90033.
Dr. Fischl: Department of Medicine, University of Miami School of Medicine, 1800 Northwest 10th Avenue, Box 016960 (R-60A), Miami, FL 33101.
Dr. Hammer: Division of Infectious Diseases, Columbia University, 630 West 168th Street, Mail Box 82, Room PH8-W876, New York, NY 10032.
Author Contributions: Conception and design: L.M. Demeter, M.D. Hughes, R.W. Coombs, S.A. Spector, M.A. Fischl, S.M. Hammer.
Analysis and interpretation of the data: L.M. Demeter, M.D. Hughes, J.M. Grimes, R.J. Bosch, S.A. Spector, M.A. Fischl, S.M. Hammer.
Drafting of the article: L.M. Demeter, M.D. Hughes, R.J. Bosch, S.A. Spector, M.A. Fischl, S.M. Hammer.
Critical revision of the article for important intellectual content: L.M. Demeter, M.D. Hughes, R.W. Coombs, J.B. Jackson, R.J. Bosch, S.A. Spector, K.E. Squires, M.A. Fischl, S.M. Hammer.
Final approval of the article: L.M. Demeter, M.D. Hughes, R.J. Bosch, S.A. Fiscus, S.A. Spector, K.E. Squires, M.A. Fischl, S.M. Hammer.
Provision of study materials or patients: J.B. Jackson, S.A. Spector, K.E. Squires, M.A. Fischl, S.M. Hammer.
Statistical expertise: M.D. Hughes, J.M. Grimes, R.J. Bosch.
Administrative, technical, or logistic support: M.D. Hughes, R.W. Coombs, J.B. Jackson, S.A. Fiscus, S.M. Hammer.
Collection and assembly of data: L.M. Demeter, M.D. Hughes, R.W. Coombs, J.M. Grimes, S.A. Spector, M.A. Fischl, S.M. Hammer.